Aromatic analogs of 4,5,13,14-tetradehydro-PGI1 compounds

ABSTRACT

The present invention relates to certain structural and pharmacological analogs of prostacyclin (PGI 2 ) which are aromatic analogs of 4,5,13,14-tetradehydro-PGI 1  compounds. These novel pharmacological agents are useful as smooth muscle stimulators.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a continuation-in-part application of Ser. No. 821,536, filed Aug. 3, 1977, now pending issuance as a United States Patent.

The present invention relates to prostacyclin analogs, for which the essential material constituting disclosure therefor is incorporated by reference here from Ser. No. 821,541, filed Aug. 3, 1977, now U.S. Pat. No. 4,109,082, issued Aug. 22, 1978. 

I claim:
 1. A prostacyclin analog of the formula ##STR1## wherein Y₂ is --C.tbd.C--; wherein Z₂ is ##STR2## wherein g is the integer zero, one, or 2; wherein M₁ is ##STR3## wherein R₅ is hydrogen or alkyl with one to 4 carbon atoms, inclusive,wherein L₁ is ##STR4## or a mixture of ##STR5## wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is fluoro only when the other is hydrogen or fluoro; wherein R₁ is hydrogen; alkyl of one to 12 carbon atoms, inclusive; cycloalkyl of 3 to 10 carbon atoms, inclusive; aralkyl of 7 to 12 carbon atoms, inclusive; phenyl; phenyl substituted with one, two or three chloro or alkyl of one to 3 carbon atoms; phenyl substituted in the para position by ##STR6## wherein R₂₅ is methyl, phenyl, acetamidophenyl, benzamidophenyl, or --NH₂ ; R₂₆ is methyl, phenyl, --NH₂, or methoxy; and R₂₇ is hydrogen or acetamido; inclusive, i.e., ##STR7## phenacyl substituted in the para position by chloro, bromo, phenyl, or benazmido; or a pharmacologically acceptable cation; and wherein Z₃ is oxa or --(CH₂)_(h) --, wherein h is the integer zero to 3, inclusive; wherein s is the integer zero, one, 2, or 3, and T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with the proviso that not more than two T's are other than alkyl.
 2. A prostacyclin analog according to claim 1, wherein Z₃ is oxa.
 3. A prostacyclin analog according to claim 2, wherein Z₂ is a mixture of ##STR8##
 4. trans-4,5,13,14-Tetradehydro-(6RS)-16-phenoxy-17,18,19,20-tetranor-PGI.sub.1, a prostacyclin analog according to claim
 3. 5. A prostacyclin analog according to claim 2, wherein Z₂ is ##STR9##
 6. trans-4,5,13,14-Tetradehydro-16-phenoxy-17,18,19,20-tetranor-6α-PGI₁, a prostacyclin analog according to claim
 5. 7. 15-Methyl-trans-4,5,13,14-tetradehydro-16-phenoxy-17,18,19,20-tetranor-6α-PGI₁, a prostacyclin analog according to claim
 5. 8. 16-Methyl-trans-4,5,13,14-tetradehydro-16-phenoxy-18,19,20-trinor-6α-PGI₁, a prostacyclin analog according to claim
 5. 9. 16,16-Difluoro-trans-4,5,13,14-tetradehydro-16-phenoxy-17,18,19,20-tetranor-6α-PGI₁, a prostacyclin analog according to claim
 5. 10. A prostacyclin analog according to claim 2, wherein Z₂ is ##STR10##
 11. A prostacyclin analog according to claim 10, wherein R₅ is methyl.
 12. 15-Methyl-trans-4,5,13,14-tetradehydro-16-phenoxy-17,18,19,20-tetranor-6β-PGI₁, a prostacyclin analog according to claim
 11. 13. A prostacyclin analog according to claim 10, wherein R₅ is hydrogen.
 14. A prostacyclin analog according to claim 13, wherein at least one of R₃ and R₄ is fluoro.
 15. 16,16-Difluoro-trans-4,5,13,14-tetradehydro-16-phenoxy-17,18,19,20-tetranor-6β-PGI-₁, a prostacyclin analog according to claim
 14. 16. A prostacyclin analog according to claim 13, wherein at least one of R₃ and R₄ is methyl.
 17. 16-methyl-trans-4,5,13,14-tetradehydro-16-phenoxy-18,19,20-trinor-6β-PGI₁, a prostacyclin analog according to claim
 16. 18. A prostacyclin analog according to claim 13, wherein R₃ and R₄ are both hydrogen.
 19. trans-4,5,13,14-Tetradehydro-16-phenoxy-17,18,19,20-tetranor-6β-PGI₁, methyl ester, a prostacyclin analog according to claim
 18. 20. trans-4,5,13,14-Tetradehydro-16-phenoxy-17,18,19,20-tetranor-6β-PGI₁, tris(hydroxymethyl)amino methane salt, a prostacyclin analog according to claim
 18. 21. trans-4,5,13,14-Tetradehydro-16-phenoxy-17,18,19,20-tetranor-6β-PGI₁, adamantanamine salt, a prostacyclin analog according to claim
 18. 22. trans-4,5,13,14-Tetradehydro-16-phenoxy-17,18,19,20-tetranor-6β-PGI₁, a prostacyclin analog according to claim
 18. 23. A prostacyclin analog according to claim 1, wherein Z₃ is --(CH₂)_(h) --.
 24. A prostacyclin analog according to claim 23, wherein Z₂ is a mixture of ##STR11##
 25. trans-4,5,13,14-Tetradehydro-(6RS)-17-phenyl-18,19,20-trinor-6α-PGI₁, a prostacyclin analog according to claim
 24. 26. A prostacyclin analog according to claim 23, wherein Z₂ is ##STR12##
 27. trans-4,5,13,14-Tetradehydro-17-phenyl-18,19,20-trinor-6α PGI₁, a prostacyclin analog according to claim
 26. 28. 15-Methyl-trans-4,5,13,14-tetradehydro-17-phenyl-18,19,20-trinor-6α-PGI₁, a prostacyclin analog according to claim
 26. 29.16,16-Dimethyl-trans-4,5,13,14-tetradehydro-17-phenyl-18,19,20-trinor-6.alpha.-PGI₁, a prostacyclin analog according to claim
 26. 30. 16,16-Difluoro-trans-4,5,13,14-tetradehydro-17-phenyl-18,19,20-trinor-6α-PGI₁, a prostacyclin analog according to claim
 26. 31. A prostacyclin analog according to claim 23, wherein Z₂ is ##STR13##
 32. A prostacyclin analog according to claim 31, wherein R₅ is methyl.
 33. 15-Methyl-trans-4,5,13,14-tetradehydro-17-phenyl-18,19,20-trinor-6.beta.-PGI₁, a prostacyclin analog according to claim
 32. 34. A prostacyclin analog according to claim 31, wherein R₅ is hydrogen.
 35. A prostacyclin analog according to claim 34, wherein at least one of R₃ and R₄ is fluoro.
 36. 16,16-Difluoro-trans-4,5,13,14-tetradehydro-17-phenyl-18,19,20-trinor-6β-PGI₁, a prostacyclin analog according to claim
 35. 37. A prostacyclin analog according to claim 34, wherein at least one of R₃ and R₄ is methyl.
 38. 16,16-Dimethyl-trans-4,5,13,14-tetradehydro-17-phenyl-18,19,20-trinor-6β-PGI₁, a prostacyclin analog according to claim
 37. 39. A prostacyclin analog according to claim 34, wherein R₃ and R₄ are both hydrogen.
 40. trans-4,5,13,14-Tetradehydro-17-phenyl-18,19,20-trinor-6β-PGI₁, methyl ester, a prostacyclin analog according to claim
 39. 41. trans-4,5,13,14-Tetradehydro-17-phenyl-18,19,20-trinor-6β-PGI₁, tris(hydroxymethyl)amino methane salt, a prostacyclin analog according to claim
 39. 42. trans-4,5,13,14-Tetradehydro-17-phenyl-18,19,20-trinor-6β-PGI₁, adamantanamine salt, a prostacyclin analog according to claim
 39. 43. trans-4,5,13,14-Tetradehydro-17-phenyl-18,19,20-trinor-6β-PGI₁, a prostacyclin analog according to claim
 39. 